A placebo-controlled, double-blind, randomized study of recombinant thrombomodulin (ART-123) to prevent oxaliplatin-induced peripheral neuropathy

Masahito Kotaka, Yoji Saito, Takeshi Kato, Hironaga Satake, Akitaka Makiyama, Yasushi Tsuji, Katsunori Shinozaki, Toshiyoshi Fujiwara, Tsunekazu Mizushima, Yasushi Harihara, Naoki Nagata, Naoto Kurihara, Masahiko Ando, Genichi Kusakawa, Takumi Sakai, Yugo Uchida, Mikihiro Takamoto, Saki Kimoto, Ichinosuke Hyodo

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: The purpose of this clinical study was to be the first to explore whether ART-123, a recombinant human soluble thrombomodulin, prevents oxaliplatin-induced peripheral neuropathy (OIPN). Methods: This randomized, phase IIa trial enrolled stage II/III colon cancer patients who received adjuvant mFOLFOX6 chemotherapy. Participants were randomly allocated to 3 arms in a double-blind manner: placebo (placebo: days 1–3); 1-day ART (ART-123: day 1, placebo: days 2–3); and 3-day ART (ART-123: days 1–3). ART-123 (380 U/kg/day) or placebo was infused intravenously before each 2-week cycle of mFOLFOX6. OIPN was assessed with the Functional Assessment of Cancer Therapy/Gynecological Oncology Group-Neurotoxicity-12 (FACT/GOG-Ntx-12) score by participants and the NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE) by investigators. Results: Seventy-nine participants (placebo n = 28, 1-day ART n = 27, 3-day ART n = 24) received study drugs. The least-squares mean FACT/GOG-Ntx-12 scores at cycle 12 from the mixed effect model for repeated measures were 28.9 with placebo, 36.3 with 1-day ART (vs. placebo: 7.3 [95% CI 1.9 to12.8, p = 0.009]), and 32.3 with 3-day ART (vs. placebo: 3.4 [95% CI −.1 to 9.0, p = 0.222]). The cumulative incidence of NCI-CTCAE grade ≥ 2 sensory neuropathy at cycle 12 was 64.3% with placebo, 40.7% with 1-day ART (vs. placebo: −23.5 [95% CI −48.4 to 4.0], p = 0.108), and 45.8% with 3-day ART (vs. placebo: −18.5 [95% CI −44.2 to 9.4], p = 0.264). Common adverse events were consistent with those reported with mFOLFOX6; no severe bleeding adverse events occurred. Conclusion: ART-123 showed a potential preventive effect against OIPN with good tolerability. A larger study with 1-day ART is warranted. NCT02792842, registration date: June 8, 2016

Original languageEnglish
JournalCancer Chemotherapy and Pharmacology
DOIs
Publication statusAccepted/In press - 2020

Keywords

  • Adjuvant chemotherapy
  • CIPN
  • Colon cancer
  • Neuropathy
  • Oxaliplatin
  • Thrombomodulin

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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